Identification of Aszonalenin Derivatives as α-Glucosidase Inhibitors from Neosartorya fischeri NRRL 181
Identification of Aszonalenin Derivatives as α-Glucosidase Inhibitors from Neosartorya fischeri NRRL 181
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DOI：
10.1007/s10600-020-03149-1
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发表时间：
2020-07
影响因子：
0.8
通讯作者：
Shilei Wang;Hang-Fei Yu;Yi-Lian Xu;Ting Tian;Z. Zhan;W. Shan;Youmin Ying
中科院分区：
文献类型：
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作者：
Shilei Wang;Hang-Fei Yu;Yi-Lian Xu;Ting Tian;Z. Zhan;W. Shan;Youmin Ying
糖尿病是一种由碳水化合物代谢异常引起的慢性代谢障碍，并因胰岛素分泌、作用或两者的决定而导致高血糖状态[1]。2型糖尿病是最常见的糖尿病形式，占所有病例的80 - 90%[2]。α-葡萄糖苷酶在碳水化合物代谢中起重要作用，因此是治疗糖尿病，特别是2型糖尿病的有吸引力的治疗靶点[1]。目前，有四种α-葡萄糖苷酶抑制剂用于治疗：阿卡波糖、米格列醇、伏格列波糖和emiglitate [3]。然而，这些抑制剂与副作用如肠胃气胀、腹痛和腹泻有关。这就需要开发副作用最小、疗效更好的新型α-葡萄糖苷酶抑制剂。作为我们正在进行的探索新型α-葡萄糖苷酶抑制剂天然产物的努力的一部分[4 - 9]，我们研究了真菌衍生的环二肽，其显示出有效的活性并引起了我们的注意[7]。在本工作中，一株多化合物（OSMAC）该策略应用于真菌Neosatorya fischeri NRRL 181，其基因组被测序并注释为含有负责生物合成的基因簇环二肽。根据紫外吸收光谱的特征，从该菌中分离得到了3个aszonalenin衍生物1-3，并对其结构进行了初步鉴定。化合物1 - 3与从A.在我们以前的研究中，terreus [10]。与阳性对照阿卡波糖相比，化合物1、2和4表现出有效的α-葡糖苷酶抑制活性（表1）。初步探讨了构效关系。据我们所知，这是第一次报道aszonalenin衍生物作为α-葡萄糖苷酶抑制剂。此外，Lineweaver-Burk图实验的结果表明，化合物1以非竞争性方式抑制α-葡糖苷酶的活性，这与已知为α-葡糖苷酶的竞争性抑制剂的阿卡波糖不同（图1）。
Diabetes is a chronic metabolic disorder caused by abnormal carbohydrate metabolism with a consequent hyperglycemia status, occurring from deciencies in insulin secretion, action, or both [1]. Type 2 diabetes is the most common form of diabetes, comprising 80–90% of all the cases [2]. α-Glucosidase plays an important role in carbohydrate metabolism and is therefore an attractive therapeutic target for the treatment of diabetes, especially type 2 diabetes [1]. Currently, four α-glucosidase inhibitors are therapeutically used: acarbose, miglitol, voglibose, and emiglitate [3]. However, these inhibitors are associated with side-effects such as flatulence, abdominal pain, and diarrhea. This demands the need for the development of new α-glucosidase inhibitors with minimal side effects and better efficacy. As part of our ongoing endeavor in exploring natural products for novel α-glucosidase inhibitors [4–9], we studied the fungal-derived cyclodipeptides, which showed potent activity and attracted our attention [7].In the present work, the one strain many compounds (OSMAC) strategy was applied to the fungus Neosatorya fischeri NRRL 181 whose genome was sequenced and annotated to harbor gene clusters responsible for the biosynthesis of cyclodipeptides. As guided by the characteristic UV absorptions, three aszonalenin derivatives 1–3were isolated and charicterized from the fungus cultured in liquid medium containing 20 g/L dextrose, 10 g/L malt extract, and 4 g/L yeast extract. Compounds 1–3 were evaluated for the in vitro α-glucosidase inhibitory activity together with a structurally related compound asterrelenin (4) that was obtained from A. terreus in our previous study [10]. Compounds 1, 2, and 4 exhibited potent α-glucosidase inhibitory activity as compared with the positive control acarbose (Table 1). The preliminary structure–activity relationship was discussed. To the best of our knowledge, this is the first report of aszonalenin derivatives as α-glucosidase inhibitors. In addition, results of the Lineweaver-Burk plots experiment suggested that compound 1 inhibited the activity of α-glucosidase in a noncompetitive manner, which is different from acarbose, known as a competitive inhibitor of α-glucosidase (Fig. 1).